Optimizing intrauterine insemination: A systematic review and meta-analysis of the effectiveness and safety of clinical treatment add-ons.

INTRODUCTION: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment. MATERIAL AND METHODS: Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857. RESULTS: Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions. CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Isolated fallopian tube torsion: A systematic review of case reports.

OBJECTIVE: To combine all literature describing cases of isolated fallopian tube torsion in adult non pregnant patients in a systematic manner, to optimize knowledge and practice both for diagnosis and management. STUDY DESIGN: EMBASE and PubMed databases were searched for the terms 'tubal' OR 'fallopian tube' AND 'isolated' AND 'torsion' from the inception of these databases to July 5, 2023. All case reports or case series of adult patients (18 years or older) with isolated fallopian tube torsion were included. Exclusion criteria included: all other study types; cases involving children and adolescents (less than 18 years old); pregnant patients of all trimesters; tubo-ovarian torsion; studies not published in English; duplicates and those not available in text. Following the database search, two authors independently screened the studies and search results were subsequently reported in accordance with PRISMA guidelines. Data was extracted independently by two authors and analysed using Excel. All cases were assessed for bias using a modified version of the tool proposed by Murad et al. RESULTS: 92 unique articles enrolling 131 individual cases were included in this systematic review. Isolated fallopian tube torsion most commonly occurs during reproductive ages between 18 and 45 years. It is uncommon in postmenopausal women. The most common presenting symptoms include unilateral lower abdominal or pelvic pain along the affected side with nausea and vomiting. Risk factors can be intrinsic or extrinsic and can include conditions such as hydrosalpinx, sterilization, pelvic inflammatory disease or cysts. Ultrasound is the optimal imaging modality however Computed Tomography and Magnetic Resonance Imaging can also be used. Imaging in general has low sensitivity, however isolated fallopian tube torsion can be identified with appropriate expertise. The gold standard for isolated fallopian tube torsion management is laparoscopy and detorsion however currently, the most common intervention performed is salpingectomy. CONCLUSIONS: Isolated fallopian tube torsion is a rare but important gynaecological emergency with significant fertility implications. This study summarizes the most common presentations, investigation findings and surgical interventions in patients with isolated fallopian tube torsion. This study also emphasizes the importance of clinicians maintaining a high degree of suspicion and low threshold for early laparoscopic intervention to retain fertility.

The definition of unexplained infertility: A systematic review.

BACKGROUND: There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice. OBJECTIVES: This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis. SEARCH STRATEGY: CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language. DATA COLLECTION AND ANALYSIS: Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range. MAIN RESULTS: Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies. CONCLUSIONS: This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.

Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.

OBJECTIVE: How do numbers of oocytes retrieved per In vitro fertilisation (IVF) cycle impact on the live birth rate (LBR) and multiple gestation pregnancy (MGP) rates? DESIGN: Retrospective observational longitudinal study. SETTING: UK IVF clinics. POPULATION: Non-donor IVF patients. MAIN OUTCOME MEASURES: LBR per IVF cycle and MGP levels against number of oocytes retrieved into subgroups: 0, 1-5, 6-15, 16-25, 26-49 oocytes and 50+ oocytes. Relative risk (RR) and 95% CIs were calculated for each group against the intermediate responder with '6-15 oocytes collected'. RESULTS: From 172 341 attempted fresh oocyte retrieval cycles, the oocyte retrieved was: 0 in 10 148 (5.9%) cycles from 9439 patients; 1-5 oocytes in 42 574 cycles (24.7%); 6-15 oocytes in 91 797 cycles (53.3%); 16-25 oocytes in 23 794 cycles (13.8%); 26-49 oocytes in 3970 cycles (2.3%); ≥50 oocytes in 58 cycles (0.033%). The LBRs for the 1-5, 6-15, 16-25 and 26-49 subgroups of oocytes retrieved were 17.2%, 32.4%, 35.3% and 18.7%, respectively. The RR (95% CI) of live birth in comparison to the intermediate group (6-15) for 1-5, 16-25 and 26-49 groups was 0.53 (0.52 to 0.54), 1.09 (1.07 to 1.11) and 0.58 (0.54 to 0.62), respectively. The corresponding MGP rates and RR were 9.2%, 11.0%, 11.4% and 11.3%, respectively and 0.83 (0.77 to 0.90), 1.04 (0.97 to 1.11) and 1.03 (0.84 to 1.26), respectively. CONCLUSION: There was only limited benefit in LBR beyond the 6-15 oocyte group going to the 16-25 oocytes group, after which there was significant decline in LBR. The MGP risk was lower in 1-5 group.

Endogenous progesterone in unexplained infertility: a systematic review and meta-analysis.

PURPOSE: To investigate the possibility that altered actions of endogenous progesterone affect receptivity and contribute to unexplained infertility (UI). METHODS: Two authors electronically searched MEDLINE, CINAHL and Embase databases from inception to 6 July 2022 and hand-searched according to Cochrane methodology. We included all published primary research reporting outcomes related to endogenous progesterone in natural cycles in women with UI. Studies were assessed for risk of bias using a modified Newcastle-Ottawa Score or NHLBI Score. We pooled results where appropriate using a random-effects model. Findings were reported as odds ratios or mean differences. RESULTS: We included 41 studies (n = 4023). No difference was found between the mid-luteal serum progesterone levels of women with UI compared to fertile controls (MD 0.74, - 0.31-1.79, I2 36%). Women with UI had significantly higher rates of 'out-of-phase' endometrium than controls. Nine out of 10 progesterone-mediated markers of endometrial receptivity were significantly reduced in women with UI compared to fertile controls (the remaining 1 had conflicting results). Resistance in pelvic vessels was increased and perfusion of the endometrium and sub-endometrium reduced in UI compared to fertile controls in all included studies. Progesterone receptor expression and progesterone uptake were also reduced in women with unexplained infertility. CONCLUSIONS: End-organ measures of endogenous progesterone activity are reduced in women with UI compared to fertile controls. This apparently receptor-mediated reduction in response affects endometrial receptivity and is implicated as the cause of the infertility. Further research is required to confirm whether intervention could overcome this issue, offering a new option for treating unexplained infertility. TRIAL REGISTRATION: PROSPERO registration: CRD42020141041 06/08/2020.

Effects of metformin treatment on pregnancy outcomes in patients with polycystic ovary syndrome.

INTRODUCTION: This review covers the current evidence regarding the use of metformin as a therapeutic intervention for optimizing pregnancy outcomes in women with polycystic ovary syndrome (PCOS). AREAS COVERED: After searching Medline, Embase and CINAHL, all important large clinical trials and observational studies plus systematic reviews, meta-analyses and Cochrane reviews have been summarized here. The results have been compared to culminate in a thorough review and discussion on the use of metformin in relation to reproductive outcomes for women with PCOS. The role of metformin in PCOS is explored both in terms of achieving conception and during pregnancy. The existing evidence around metformin use is summarized both during the preconceptual period and during pregnancy, in relation to reproductive outcomes. EXPERT OPINION: Metformin is a widely used medication, often prescribed to improve reproductive outcomes for women with PCOS. However, the evidence remains equivocal regarding its efficacy both in optimizing fertility and pregnancy outcomes. More research is required with special emphasis on metformin use within different populations, including ethnic groups and women with varying BMI ranges.

Preconception tests at advanced maternal age.

Pregnancies at an advanced reproductive age are increasingly common. However, the safety of pregnancy remains a concern as maternal age is a recognized independent factor for various obstetric complications. Also, age is a risk factor for most systematic health problems and older women are more likely to enter into pregnancy with pre-existing conditions. At the moment there is no separate, structured guidance on preconception tests at advanced maternal age. However, the preconceptual period offers an ideal window to recognize and address underlying health issues, social issues and harmful lifestyle behaviours in order to optimize maternal health ultimately reducing infertility, perinatal morbidity and mortality. Preconception tests should be clinically relevant aiming to identify risk factors and address them to predict and prevent infertility and pregnancy complications. The importance of preconception care is magnified for women of advanced age for whom the risks are higher and the potential benefits greater.

The Source of Polycystic Ovarian Syndrome.

The source of polycystic ovarian syndrome (PCOS) is much debated and is likely to be multifactorial. There is an apparent familial inheritance with first-degree relatives of sufferers more likely to be affected. Twin studies have suggested a genetic cause but candidate genes are yet to be verified. Genes affecting insulin resistance, steroid hormone production, and inflammatory cytokine responses have all been implicated. Current thinking supports the theory that exposure to environmental factors in utero predisposes a female foetus to hyperandrogenism, insulin resistance, and polycystic ovaries in adult life. Which environmental factors have an impact on the foetus and the mechanisms of exposure are still to be confirmed. Animal studies have shown a clear correlation between hyperexposure of the foetus to androgens in utero and future development of a PCOS pattern of symptoms. Placental aromatases should neutralise androgens from the maternal circulation and prevent them reaching the foetal circulation. Our hypothesis is that the high maternal anti-Mullerian hormone (AMH) levels in PCOS block the placental aromatase and allow passage of testosterone through the placenta. This maternal testosterone acts on the foetal ovaries and 'programmes' them to recruit more preantral follicles and so produce higher AMH levels when they become functional at around 36 weeks of gestation. The high AMH concentrations in PCOS also seem to increase luteinizing hormone release and inhibit follicle stimulating hormone action on aromatase, so adding to the hyperandrogenic environment of adult PCOS.